While there is evidence that activities in the motor cortex of the hemisphere contralateral to the stroke (contralesional M1) will impact the extent of motor function of the paretic limb in the subacute and chronic phase post-stroke, the precise factors that specifically influence those events and how they relate to recovery of motor function remain to be defined. A better understanding of those events is critical to development of optimal therapeutic strategies such as non-invasive stimulation protocols to improve functional recovery following stroke. The objectives in this application are to systematically study the effects of stimulation of contralesional M1 in order to define the factors that influence contralesional M1 excitability as it relates to motor function post-stroke, and build on this information to develop strategies that specifically target excitability changes in contralesional M1 to enhance recovery of stroke patients. In a longitudinal study of stroke patients, contralesional M1 reorganization and stimulation will be assessed in three Specific Aims. In the first Specific Aim, we will determine the extent of functional and structural contralesional M1 reorganization using complementary techniques of transcranial magnetic stimulation (TMS), functional and structural MRI of the brain. In the second Specific Aim, the contribution of contralesional M1 reorganization to the recovery of motor function will be studied. Repetitive TMS will be used to transiently disrupt contralesional M1 function, thereby determine its role for the motor performance of the paretic limb. RTMS related improvement of motor performance would identify a supportive role of contralesional M1 while deterioration of motor performance would indicate its detrimental role. In Specific Aim #3, different rTMS protocols will be applied to contralesional M1 to determine whether M1 can be primed to enhance restorative therapy. Specifically, contralesional M1 excitability will be increased when its role is supportive and decreased when its role is detrimental. At the completion of this project, it is our expectation that we will have determined the extent to which contralesional M1 activity determines recovery and motor performance post-stroke. We also expect to have identified the feasibility of interventions designed specifically to target the different "states" of contralesional M1. This latter knowledge would be expected to have a substantial positive impact on treatment for stroke patients that will significantly improve their functional recovery.